The tumor necrosis factor α (TNFα) a member of the tumor necrosis factor superfamily, has biological activities of modulating immunological response, cell apoptosis, cell differentiation, and the like. TNFα has two intracellular receptors, TNF receptor 1 (TNFRp55) and TNF receptor 2 (TNFRp75). Overproduction of TNFα is an underlying mechanism of autoimmune diseases such as rheumatoid arthritis. Blocking excess TNFa by its antagonists including soluble TNFRp75:Fc fusion proteins such as Etanercept and anti-TNF monoclonal antibodies such as Infliximab has been validated as an effective treatment for rheumatoid arthritis.
Etanercept can bind both TNFα and lymphotoxin (LT), but it requires a relatively large clinical dose at about 25-50 mg, which tends to cause erythema when administered via subcutaneous injection. Therefore, it is highly demanded to develop a TNFRp75 which can bind TNF and lymphotoxin with high affinity, and in turn to develop a TNFRp75:Fc fusion protein as an antibody drug.